1. Field of the Invention
The invention relates to chemically defined polymeric carriers that provide advantageous properties for in vivo imaging and therapy. The polymeric carriers consist of .alpha.-amino acids that contain side chains covalently joined to (i) diagnostic and therapeutic molecules and (ii) chelating agents capable of binding diagnostic or therapeutic radionuclides.
2. Related Art
Monoclonal antibodies have been developed that localize in cancerous tissue, due to their high specificity and affinity for antigens on tumor cell surfaces. This development has increased the prospect of clinical applications, if such antibodies can be linked to diagnostic and therapeutic agents. The high specificity of the antibodies makes them desirable candidates as targeting molecules for delivering a diagnostic or therapeutic agent to a cancer site.
Unfortunately, the direct linkage of such agents to an antibody beyond an optimum level reduces its immunoreactivity and targeting ability. Any excessive derivatization results in lower immunoreactivity and targeting. In the present art, chelating agents capable of binding to diagnostic and therapeutic isotopes and cytotoxic agents are attached to antibodies in the following manner:
a) direct attachment to antibodies (e.g.) .alpha.-amino groups of lysine; PA1 b) direct attachment to antibodies via cleavable linker; and PA1 c) the agents attached to a heterogeneous homopolymer such as polylysine, which in turn is attached to antibodies.
Direct attachment of therapeutic agents to proteins produces metabolities that have a high affinity to be excreted into the gut or retained by the kidney. In order to overcome this problem, the agents are attached via a clearable linker. This approach markedly reduces toxicity in the gut and kidney because of renal excretion of the agents. However, this procedure cannot deliver a therapeutic dose of such compounds. The use of polylysine as a carrier, while permitting an increased amount of therapeutic agents to be carried to the target, does not provide definition of product and is subject to variations. Since the linkage between the agent and carrier and the linkage between carrier and protein is less defined, rational variation of the rate of release of agents is not possible. Therefore, this approach precludes controlled release of a therapeutic molecule.
What is needed is an approach that derivatizes a targeting molecule such as an antibody or other proteins (growth factors) at a minimum number of sites to preserve high immunoreactivity and targeting ability. Such a procedure should be able to carry a therapeutic dose of a radionuclide-chelate or cytotoxic agent. Also needed, is an approach in which "chemically defined" polymers attached to antibodies carry therapeutic doses of agents from which the agent can be released in the native state to be efficacious. Such polymers attached to antibodies provide a complete definition of the product to meet the requirements of the regulatory process. By adjusting the "nature" of the "clearable linker" between therapeutic molecule and "chemically defined polymer" one can carry high doses of therapeutic molecules and release them at a desired site. Such a tailor-made "chemically defined" polymeric carrier unlike a heterogeneous homopolymer can incorporate functional groups to provide solubility. This is important when highly efficacious cytotoxic but lipid soluble drugs need to be employed.